Obesity is a major health problem in the USA and the accumulated health cost due to obesity alone was reported to be ~80 billion USD in the year 2010, which is projected to cross 350 billion USD by the year 2025. Research in the last two decades has shown that in majority of the cases obesity is due to energy surplus and can be treated by increasing energy expenditure. In spite of significant progress in the understanding about ways to target cellular bioenergetics to increase energy expenditure most of these are reliant on uncoupling protein 1 (UCP1)-based mechanisms, that is a minor component in most adult human beings. Therefore, alternative mechanism of thermogenesis should be paid equal importance to enhance energy expenditure to treat obesity. We have recently discovered a novel thermogenic mechanism by a protein called Sarcolipin (SLN), published in Nature Medicine in 2012. SLN is a 31 amino acid single transmembrane protein, that regulate the function of SERCA pump. Binding of SLN to SERCA promotes uncouple ATP hydrolysis of SERCA pump from Ca2+ transport leading to futile cycling and increased ATP utilization contributing to muscle-based non-shivering thermogenesis (NST). We have shown that loss of SLN predisposes mice to develop obesity on high fat diet (HFD) but upregulation of SLN provide protection against HFD-induced obesity. Our next study shows that skeletal muscle specific overexpression of SLN drives mitochondrial biogenesis and fuels oxidative metabolism in skeletal muscle providing resistance to obesity, is under final stages of publication. Further, genetic alteration in chromosomal locus containing SLN has also been shown to be associated with obesity in humans, suggesting SLN-mediated energy consumption may be a factor in obesity. Skeletal muscle constitutes ~40% of mammalian body mass and accounts for ~80% of metabolic substrate consumption. Therefore skeletal muscle offers an ideal target to increase energy expenditure, pharmacologically as a strategy for the treatment of obesity. In this application, I propose to identify lead compounds enhancing SLN-mediated skeletal muscle-based energy expenditure, using a multifaceted approach including studies at the whole animal, tissue, cell and computational levels. I have data to indicate that capsaicin enhances SLN-SERCA binding. I have also developed a cell-based assay to screen compounds with ability to enhance SLN-mediated uncoupling of SERCA. I have designed and synthesized four different capsaicin analogs, by modifying the side-chains. My preliminary data suggest that one these four capsaicin-analogs possess better activity than capsaicin itself. These facts provide more confidence in my initial hypothesis and I propose the following three aims towards achieving my final goal. In Aim 1, I will try to identify the best capsaicin-analog to increase SLN-mediated energy expenditure and anti- obesity lead. In Aim 2, I will further explore other classes of compounds (many chemical libraries are available in college of pharmacy on campus) known to affect SERCA function and/or increase energy consumption, to Identify chemicals that increase SLN-mediated uncoupling of SERCA and possess anti-obesity activity. In AIM 3, I am working to develop a responsive atomistic model of SLN-SERCA-ligand interaction to define the pharmacophores and optimize the shortlisted anti-obesity agents. We believe that identification of chemical compounds with ability to enhance SLN action on SERCA will provide an exciting new opportunity to pharmacologically increase muscle-based energy consumption and control obesity.